Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Multifunctional organoboron compounds for scalable natural product synthesis

Nature volume 513, pages 367–374 (2014)Cite this article

Subjects

Abstract

Efficient catalytic reactions that can generate C–C bonds enantioselectively, and ones that can produce trisubstituted alkenes diastereoselectively, are central to research in organic chemistry. Transformations that accomplish these two tasks simultaneously are in high demand, particularly if the catalysts, substrates and reagents are inexpensive and if the reaction conditions are mild. Here we report a facile multicomponent catalytic process that begins with a chemoselective, site-selective and diastereoselective copper–boron addition to a monosubstituted allene; the resulting boron-substituted organocopper intermediates then participate in a similarly selective allylic substitution. The products, which contain a stereogenic carbon centre, a monosubstituted alkene and an easily functionalizable Z-trisubstituted alkenylboron group, are obtained in up to 89 per cent yield, with more than 98 per cent branch-selectivity and stereoselectivity and an enantiomeric ratio greater than 99:1. The copper-based catalyst is derived from a robust heterocyclic salt that can be prepared in multigram quantities from inexpensive starting materials and without costly purification procedures. The utility of the approach is demonstrated through enantioselective synthesis of gram quantities of two natural products, namely rottnestol and herboxidiene (also known as GEX1A).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Multicomponent catalytic enantioselective generation of alkenylboron compounds.
Figure 2: Catalytic chemo-, site- and enantioselective multicomponent reactions.
Figure 3: Origins of high efficiency and selectivity.
Figure 4: Enantioselective gram-scale synthesis of rottnestol.
Figure 5: Enantioselective gram-scale synthesis of herboxidiene.

Similar content being viewed by others

References

  1. Ramón, D. J. & Yus, M. Asymmetric multicomponent reactions (AMCRs): the new frontier. Angew. Chem. Int. Edn 44, 1602–1634 (2005)

    Article  Google Scholar 

  2. Ruijter, E., Scheffelaar, R. & Orru, R. V. A. Multicomponent reaction design in the quest for molecular complexity and diversity. Angew. Chem. Int. Edn 50, 6234–6246 (2011)

    Article  CAS  Google Scholar 

  3. Bower, J. F., Kim, I. S., Patman, R. L. & Krische, M. J. Catalytic carbonyl addition through transfer hydrogenation: a departure from preformed organometallic reagents. Angew. Chem. Int. Edn 48, 34–46 (2009)

    Article  CAS  Google Scholar 

  4. Ngai, M.-Y., Barchuk, A. & Krische, M. J. Enantioselective iridium-catalyzed imine vinylation. Optically enriched allylic amines via alkyne–imine reductive coupling mediated by hydrogen. J. Am. Chem. Soc. 129, 12644–12645 (2007)

    Article  CAS  Google Scholar 

  5. Hassan, A. & Krische, M. J. Unlocking hydrogenation for C–C bond formation: a brief overview of enantioselective methods. Org. Process Res. Dev. 15, 1236–1242 (2011)

    Article  CAS  Google Scholar 

  6. Meng, F., Jang, H., Jung, B. & Hoveyda, A. H. Cu-catalyzed chemoselective preparation of 2-(pinacolato)boron-substituted allylcopper complexes and their in situ site-, diastereo-, and enantioselective additions to aldehydes and ketones. Angew. Chem. Int. Edn 52, 5046–5051 (2013)

    Article  CAS  Google Scholar 

  7. Takano, D. et al. Total synthesis of nafuredin, a selective NADH-fumarate reductase inhibitor. Org. Lett. 3, 2289–2291 (2001)

    Article  CAS  Google Scholar 

  8. Schow, S. R., Bloom, J. D., Thompson, A. S., Winzenberg, K. N. & Smith, A. B. Milbemycin–avermectin studies. 5. Total synthesis of milbemycin β3 and its C(12) epimer. J. Am. Chem. Soc. 108, 2662–2674 (1986)

    Article  CAS  Google Scholar 

  9. Zhang, P., Le, H., Kyne, R. E. & Morken, J. P. Enantioselective construction of all-carbon quaternary centers by branch-selective Pd-catalyzed allyl–allyl cross-coupling. J. Am. Chem. Soc. 133, 9716–9719 (2011)

    Article  CAS  Google Scholar 

  10. Hornillos, V., Peréz, M., Fañanás-Mastral, M. & Feringa, B. L. Copper-catalyzed enantioselective allyl–allyl cross-coupling. J. Am. Chem. Soc. 135, 2140–2143 (2013)

    Article  CAS  Google Scholar 

  11. Hamilton, J. Y., Sarlah, D. & Carreira, E. M. Iridium-catalyzed enantioselective allyl–alkene coupling. J. Am. Chem. Soc. 136, 3006–3009 (2014)

    Article  CAS  Google Scholar 

  12. Tanaka, H. et al. Structure of FK506: a novel immunosuppressant isolated from Streptomyces. J. Am. Chem. Soc. 109, 5031–5033 (1987)

    Article  CAS  Google Scholar 

  13. Jones, T. K., Reamer, R. A., Desmond, R. & Mills, S. G. Chemistry of tricarbonyl hemiketals and application of Evans’ technology to the total synthesis of the immunosuppressant (–)-FK-506. J. Am. Chem. Soc. 112, 2998–3017 (1990)

    Article  CAS  Google Scholar 

  14. Nakatsuka, M. et al. Total synthesis of FK-506 and an FKBP probe reagent, (C8,C9-13C2)-FK-506. J. Am. Chem. Soc. 112, 5583–5601 (1990)

    Article  CAS  Google Scholar 

  15. Ireland, R. E., Gleason, J. L., Gegnas, L. D. & Highsmith, T. K. A total synthesis of FK-506. J. Org. Chem. 61, 6856–6872 (1996)

    Article  CAS  Google Scholar 

  16. Morrill, C. & Grubbs, R. H. Synthesis of functionalized vinyl boronates via ruthenium-catalyzed olefin cross-metathesis and subsequent conversion to vinyl halides. J. Org. Chem. 68, 6031–6034 (2003)

    Article  CAS  Google Scholar 

  17. Kotha, S., Lahiri, K. & Kashinath, D. Recent applications of the Suzuki-Miyaura cross-coupling reaction in organic synthesis. Tetrahedron 58, 9633–9695 (2002)

    Article  CAS  Google Scholar 

  18. Takano, D. et al. Absolute configuration of nafuredin, a new specific NADH-fumarate reductase inhibitor. Tetrahedr. Lett. 42, 3017–3020 (2001)

    Article  CAS  Google Scholar 

  19. Omura, S. et al. An anthelmintic compound, nafuredin, shows selective inhibition of complex I in helminth mitochondria. Proc. Natl Acad. Sci. USA 98, 60–62 (2001)

    Article  ADS  CAS  Google Scholar 

  20. Shoop, W. L., Mrozik, H. & Fisher, M. H. Structure and activity of avermectins and milbemycins in animal health. Vet. Parasitol. 59, 139–156 (1995)

    Article  CAS  Google Scholar 

  21. Erickson, K. L., Beutler, J. A., Cardellina, J. H. & Boyd, M. R. Rottnestol, a new hemiketal from the sponge Haliclona sp. Tetrahedron 51, 11953–11958 (1995)

    Article  CAS  Google Scholar 

  22. Hasegawa, M. et al. Identification of SAP155 as the target of GEX1A (Herboxidiene), an antitumor natural product. ACS Chem. Biol. 6, 229–233 (2011)

    Article  CAS  Google Scholar 

  23. Meng, F., Jung, B., Haeffner, F. & Hoveyda, A. H. NHC–Cu-catalyzed protoboration of monosubstituted allenes. Ligand-controlled site selectivity, application to synthesis and mechanism. Org. Lett. 15, 1414–1417 (2013)

    Article  CAS  Google Scholar 

  24. Guzman-Martinez, A. & Hoveyda, A. H. Enantioselective synthesis of allylboronates bearing a tertiary or quaternary B-substituted stereogenic carbon by NHC–Cu-catalyzed substitution reactions. J. Am. Chem. Soc. 132, 10634–10637 (2010)

    Article  CAS  Google Scholar 

  25. De Vries, A. H. M., Meetsma, A. & Feringa, B. L. Enantioselective conjugate addition of dialkylzinc reagents to cyclic and acyclic enones catalyzed by chiral copper complexes of new phosphorus amidites. Angew. Chem. Int. Edn 35, 2374–2376 (1996)

    Article  CAS  Google Scholar 

  26. Van Veldhuizen, J. J., Campbell, J. E., Giudici, R. E. & Hoveyda, A. H. A readily available chiral Ag-based N-heterocyclic carbene complex for use in efficient and highly enantioselective Ru-catalyzed olefin metathesis and Cu-catalyzed allylic alkylation reaction. J. Am. Chem. Soc. 127, 6877–6882 (2005)

    Article  CAS  Google Scholar 

  27. May, T. L., Brown, M. K. & Hoveyda, A. H. Enantioselective synthesis of all-carbon quaternary stereogenic centers by catalytic asymmetric conjugate additions of alkyl and aryl aluminum reagents to five-, six-, and seven-membered-ring β-substituted cyclic enones. Angew. Chem. Int. Edn 47, 7358–7362 (2008)

    Article  CAS  Google Scholar 

  28. Clavier, H., Coutable, L., Toupet, L., Guillemin, J.-C. & Mauduit, M. Design and synthesis of new bidentate alkoxy–NHC ligands for enantioselective copper-catalyzed conjugate addition. J. Organomet. Chem. 690, 5237–5254 (2005)

    Article  CAS  Google Scholar 

  29. Lee, Y. & Hoveyda, A. H. Efficient boron–copper additions to aryl-substituted alkenes promoted by NHC-based catalysts. Enantioselective Cu-catalyzed hydroboration reactions. J. Am. Chem. Soc. 131, 3160–3161 (2009)

    Article  CAS  Google Scholar 

  30. Díez-González, S. & Nolan, S. P. Stereoelectronic parameters associated with N-heterocyclic carbene (NHC) ligands: a quest for understanding. Coord. Chem. Rev. 251, 874–883 (2007)

    Article  Google Scholar 

  31. Maji, B., Breugst, M. & Mayr, H. N-Heterocyclic carbenes: organocatalysts with moderate nucleophilicity but extraordinarily high Lewis basicity. Angew. Chem. Int. Edn 50, 6915–6919 (2011)

    Article  CAS  Google Scholar 

  32. Denmark, S. E. & Beutner, G. L. Lewis base catalysis in organic synthesis. Angew. Chem. Int. Edn 47, 1560–1638 (2008)

    Article  CAS  Google Scholar 

  33. Yoshikai, N. & Nakamura, E. Mechanisms of nucleophilic organocopper(I) reactions. Chem. Rev. 112, 2339–2372 (2012)

    Article  CAS  Google Scholar 

  34. Jung, B. & Hoveyda, A. H. Site- and enantioselective formation of allene-bearing tertiary or quaternary carbon stereogenic centers through NHC–Cu-catalyzed allylic substitution. J. Am. Chem. Soc. 134, 1490–1493 (2012)

    Article  CAS  Google Scholar 

  35. Gao, F., Carr, J. L. & Hoveyda, A. H. A broadly applicable NHC–Cu-catalyzed approach for efficient, site-, and enantioselective coupling of readily accessible (pinacolato)alkenylboron compounds to allylic phosphates and applications to natural product synthesis. J. Am. Chem. Soc. 136, 2149–2161 (2014)

    Article  CAS  Google Scholar 

  36. Park, J. K., Lackey, H. H., Ondrusek, B. A. & McQuade, D. T. Stereoconvergent synthesis of chiral allylboronates from an E/Z mixture of allylic aryl ethers using 6-NHC–Cu(I) catalyst. J. Am. Chem. Soc. 133, 2410–2413 (2011)

    Article  CAS  Google Scholar 

  37. Lee, K.-s. & Hoveyda, A. H. Monodentate Non-C2-symmetric chiral N-heterocyclic carbene complexes for enantioselective synthesis. Cu-catalyzed conjugate additions of aryl- and alkenylsilylfluorides to cyclic enones. J. Org. Chem. 74, 4455–4462 (2009)

    Article  CAS  Google Scholar 

  38. Gao, F., Lee, Y., Mandai, K. & Hoveyda, A. H. Quaternary carbon stereogenic centers through copper-catalyzed enantioselective allylic substitutions with readily accessible aryl- or heteroaryllithium reagents and aluminum chlorides. Angew. Chem. Int. Edn 49, 8370–8374 (2010)

    Article  CAS  Google Scholar 

  39. Xu, S., Lee, C.-T., Rao, H. & Negishi, E. Highly (≥98%) stereo- and regioselective trisubstituted alkene synthesis of wide applicability via 1-halo-1-alkyne hydroboration-tandem Negishi–Suzuki coupling or organoborate migratory insertion. Adv. Synth. Catal. 353, 2981–2987 (2011)

    Article  CAS  Google Scholar 

  40. Garber, S. B., Kingsbury, J. S., Gray, B. L. & Hoveyda, A. H. Efficient and recyclable monomeric and dendritic Ru-based metathesis catalysts. J. Am. Chem. Soc. 122, 8168–8179 (2000)

    Article  CAS  Google Scholar 

  41. Jang, H., Zhugralin, A. R., Lee, Y. & Hoveyda, A. H. Highly selective methods for synthesis of internal (α-) vinylboronates through efficient NHC–Cu-catalyzed hydroboration of terminal alkynes. Utility in chemical synthesis and mechanistic basis for selectivity. J. Am. Chem. Soc. 133, 7859–7871 (2011)

    Article  CAS  Google Scholar 

  42. Fürstner, A. et al. Total synthesis of lejimalide A–D and assessment of the remarkable actin-depolymerizing capacity of these polyene macrolides. J. Am. Chem. Soc. 129, 9150–9161 (2007)

    Article  Google Scholar 

  43. Czuba, I. R., Zammit, S. & Rizzacasa, M. A. Total synthesis of marine sponge metabolites (+)-rottnestol, (+)-raspailol A and (+)-raspailol B. Org. Biomol. Chem. 1, 2044–2056 (2003)

    Article  CAS  Google Scholar 

  44. Pellicena, M., Krämer, K., Romea, P. & Urpí, F. Total synthesis of (+)-herboxidiene from two chiral lactate-derived ketones. Org. Lett. 13, 5350–5353 (2011)

    Article  CAS  Google Scholar 

  45. Murray, T. J. & Forsyth, C. J. Total synthesis of GEX1A. Org. Lett. 10, 3429–3431 (2008)

    Article  CAS  Google Scholar 

  46. Sasaki, Y., Zhong, C., Sawamura, M. & Ito, H. Copper(I)-catalyzed asymmetric monoborylation of 1,3-dienes: synthesis of enantioenriched cyclic homoallyl- and allylboronates. J. Am. Chem. Soc. 132, 1226–1227 (2010)

    Article  CAS  Google Scholar 

  47. Sasaki, Y., Horita, Y., Zhong, C., Sawamura, M. & Ito, H. Copper(I)-catalyzed regioselective monoborylation of 1,3-enynes with an internal triple bond: selective synthesis of 1,3-dienylboronates and 3-alkynylboronates. Angew. Chem. Int. Ed. 50, 2778–2782 (2011)

    Article  CAS  Google Scholar 

  48. Meng, F., Haeffner, J. & Hoveyda, A. H. Diastereo- and enantioselective reactions of bis(pinacolato)diboron, 1,3-enynes, and aldehydes catalyzed by an easily accessible bisphosphine–Cu complex. J. Am. Chem. Soc. 136, 11304–11307 (2014)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by grants from the National Institutes of Health, Institute of General Medical Sciences (GM-47480) and the National Science Foundation (CHE-1111074 and CHE-1362763). F.M. acknowledges a LaMattina graduate fellowship in organic synthesis. We thank M. J. Koh, D. L. Silverio and F. Haeffner for discussions, Boston College for access to computational facilities and Frontier Scientific, Inc., for gifts of B2(pin)2.

Author information

Authors and Affiliations

  1. Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, 02467, Massachusetts, USA

    Fanke Meng, Kevin P. McGrath & Amir H. Hoveyda

Authors
  1. Fanke Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kevin P. McGrath
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amir H. Hoveyda
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

F.M. performed the catalyst studies and method development studies, as well as the total syntheses of rottnestol and herboxidiene. K.P.M. carried out the computational studies. A.H.H. and F.M. conceived the project. A.H.H. designed and directed the investigations and composed the manuscript with revisions provided by the other authors.

Corresponding author

Correspondence to Amir H. Hoveyda.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Information parts 1 and 2. Part 1 contains data regarding catalyst and method development and Part 2 contains spectra data for catalyst and method development. (PDF 22354 kb)

Supplementary Information

This file contains Supplementary Information Part 3, containing spectra data for the total syntheses. (PDF 23626 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Meng, F., McGrath, K. & Hoveyda, A. Multifunctional organoboron compounds for scalable natural product synthesis. Nature 513, 367–374 (2014). https://doi.org/10.1038/nature13735

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature13735

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing